Protein farnesylation is the attachment of the 15-carbon farnesyl group to the C-termini of proteins in eukaryotic cells. We have shown that this post-translational modification occurs in trypanosomatids and malaria, parasites that cause devastating tropical diseases. We have also shown that the enzyme that attaches farnesyl groups to parasite proteins, protein farnesyltransferase (PFT), is a good target for the development of novel drugs that irreversibly inhibit the growth of the parasite that causes African sleeping sickness (Trypanosoma brucei) and malaria (Plasmodium falciparum). We have made considerable progress in the design and discovery of potent inhibitors of parasite PFTs that block the growth of parasites in culture and also cure experimental rodents infected with parasites. However, our best compounds are not good enough to advance into clinical trials because they are metabolized too quickly to allow for once or twice daily dosing over a 3-day period, a dose schedule that is optimal for treatment of tropical diseases. We want to continue to apply the principles of structure-guided medicinal chemistry to improve the drug-like properties of our PFT inhibitors. In vitro assessment of drug metabolism and intestinal absorption will be used to screen potent PFT inhibitors. Our best compounds will be further explored for efficacy in parasite- infected rodents. Our overall goal is to develop new drugs for the treatment of parasitic diseases that cause suffering among millions of people worldwide. PUBLIC HEALTH RELEVANCE: The relevance of our work is to discover new therapeutics for the treatment of the devastating tropical diseases malaria and African sleeping sickness. Malaria and African sleeping sickness kill about 2 million and 200,000 people, respectively, each year. New drugs are needed because existing drugs are either ineffective or resistance has developed. [unreadable] [unreadable] [unreadable]